Clinical Study Report (Annexes) PDF

CLINICAL STUDY REPORT (ANNEXES) GHPP PLUS FELLOWSHIP JOINT REGULATORY EXCELLENCE TRAINING Tanzania Medicines and Medical Devices Regulatory Authority Presenter: Diana Njiu CONTENT 1. Overview of Clinical Study Report 2. a)Types of Clinical Study Report b)Parts of the Clinical study Report 3....

CLINICAL STUDY REPORT (ANNEXES) GHPP PLUS FELLOWSHIP JOINT REGULATORY EXCELLENCE TRAINING Tanzania Medicines and Medical Devices Regulatory Authority Presenter: Diana Njiu CONTENT 1. Overview of Clinical Study Report 2. a)Types of Clinical Study Report b)Parts of the Clinical study Report 3. Annexes CONTENT Learning outcome:  To familiarize with the main parts of Clinical Study Report.  To understand important aspects to consider during the assessment of the Clinical study Report.. There are three images: Write anything that comes in your mind about which part of the clinical study report is related to the image? Mentimeter The voting code 4881 4917 https://www.mentimeter.com/app/presentation/alniepj77af39skiesbiyc7ewq8t3nsa CONTENT  Look at the picture: Before flight just at the airport… what would you need…to take note of… CONTENT CONTENT Before Clinical study trial… What document is critical? ……………………………………… This document describes exactly what the trial will consist of. CONTENT Clinical Study Protocol: present the detailed description of how the Clinical Study was carried out. CLINICAL STUDY REPORT  The trial sponsor compiles a detailed clinical study report (CSR) after each clinical trial.  A Clinical Study Reports (CSRs) are critical documents that describe the methodology and results of a clinical trial in drug development.  Information summarised from the CSR can be shared with the public through: Marketing authorisation Clinical trial registries Journal papers product information European Public Patient organisation Assessment Reports Conferences websites (EPARs) REG X 8 Lets Recap about clinical trial: PURPOSE: TYPES: PHASES:  Treatment  Effectiveness of intervention to Test new approaches to treat a disease treat a disease  Safety of a new drug  Prevention What approaches can PHASE I  Defining dose administration prevent disease PHASE II  Testing drug formulation  Early-detection/screening PHASE III What are new ways to  Exploring combination therapies PHASE IV find hidden disease  Evaluating effect of therapies on quality of life  Diagnostic How can new tests or procedures to diagnose disease suit REG X 9  CONTENT Various links of the guidelines:  ICH (international Conference on Harmonisation) http://www.ich.org/products/guidelines.html  FDA (Food and Drug Agency) (http://www.fda.gov/)  EMEA (European Medicines Agency) (http://www.emea.europa.eu/)  Canadian (https://www.canada.ca/en/health-canada/services/drugs- health-products/drug-products/applications-submissions/guidance- documents/international-conference-harmonisation/efficacy/structure- content-clinical-study-reports-topic-health-canada-1996.html)  Australian TGA (http://www.tga.gov.au /sites /default /files/clinical- trials- handbook.pdf). Clinical study report: TYPES Present a comprehensive clinical and statistical description of a Full sponsor’s study conduct. Provide additional detail to a full report of a study. Supplemental Condensed versions of the full CSR. Abbreviated Submitted for studies that are not relevant to the evaluation of Synopsis product effectiveness or clinical pharmacology. REG X 11 Scenario for abbreviated Clinical Study Report: Controlled studies examining conditions clearly unrelated to the main drug claim (i.e. failed indication) Uncontrolled studies or other studies not designed to establish efficacy (i.e. studies with different indication or dosage forms that are not being registered) Seriously flawed or aborted studies, including unsuccessful pivotal studies agreed by the FDA to be abbreviated REG X 12 Sample of CSR Report Body In the format of ICH E3 “Structure and Content of Clinical Study Reports” 1. Title page 2. Synopsis 3. Table of contents 4. List of abbreviations 5. Ethics 6. Investigators and study administrative structure 7. Introduction 8. Study objectives REG X 13  Sample of CSR Report Body In the format of ICH E3 “Structure and Cont.. Content of Clinical Study Reports” 9. Investigational plan 10. Study patients 11. Efficacy evaluation 12. Safety evaluation 13. Discussion and overall conclusions 14. Tables, figures and graphs referred to but not included in the text 15. Reference list 16. Appendices REG X 14 STRUCTURE OF FULL CSR: 10 1. TITTLE - EXERCIZE minutes Go to Breakout session: 2 groups 1. What is missing in the 1. TITTLE PAGE? 2. What is its importance having it mentioned? 3. If the clinical study report number/ date/development phase of the study is missing in the report, What will be the impact to this report during regulatory assessment? REGX 15 CONTENT 2. SYNOPSIS Summarizes the Clinical study in brief. 3. Table Of Contents For The Individual Clinical Study Report The page number or other locating information of each section, including summary tables, figures and graphs, − a list and the locations of appendices, tabulations and any case report forms should be provided. 4. List Of Abbreviations And Definition Of Terms REG X 17  5. ETHICS Independent Ethics Committee Ethical conduct Patient Information and consent 6. INVESTIGATOR AND ADMINISTRATIVE STRUCTURE Principal Investigator Monitoring and Evaluation Committee X REG 18 What About International Regulation?  E6 Good Clinical Practice (GCP): Consolidated Guidance  International ethical and scientific quality standard for designing, conducting, recording and reporting trial results.  Past transgressions lead to the need for laws that protect the rights and welfare of human subjects.  Nuremberg Doctors Trial of 1946 (Nuremberg Code)  Thalidomide Tragedy (Kefauver-Harris Amendment)  Tuskegee Experiments (Belmont Report)  Human Radiation Experiments  Gene Transfer Experiment REG X 19 Institutional Review Board: IRB All clinical trials must be approved and monitored by an IRB. IRB is an independent committee of physicians, nurses, statisticians, community advocates and others. The function of the IRB is to ensure that a clinical trial is ethical and the rights welfare of study participants are protected. REG X 20 7. INTRODUCTION 8. STUDY OBJECTIVES A brief statement (maximum: 1 page) placing the study in the context of the development A statement describing the overall purposes of the test drug/investigational product, of the study should be provided. relating the critical features of the study. REG X 21 INVESTIGATIONAL PLAN: Exercise (10 minutes) Explain your answer Read (Yes/No) statements Go to miro on stick board papers Select the terms that relate to the information under investigational plan in the clinical study. REG X 22 EXERCIZE - MIRO BOARD REGX 23  Investigational Plan 9.1 Overall study design and plan should consider treatments studied (specific drugs, doses and procedures), patient population studied and the number of patients to be included, level and method of blinding and the controls. 9.2 Discussion of study design and choice of control groups: The specific control chosen and the study design used. 9.3 Selection of Study Population: Inclusion Criteria and Exclusion Criteria, Removal of patients from therapy or assessment. 9.4 Treatments: Treatment administered, Identity of Investigational Product In the text of the report, a brief description of the test drug(s) /investigational product(s) (formulation, strength, batch number(s) should be given. Method of Assigning Patients to Treatment Groups. 9.5 Efficacy and safety variables schedule (days of study, time of day, relation to meals, and the timing of critical measures in relation to test drug administration. X REG 24 When reviewing the inclusion and exclusion criteria: Patient Recruitment Challenges  Poor patient recruitment  Patients being referred found not qualified for the study.  Lack of awareness about clinical trials in patients.  Complexity of study protocol.  Social and cultural issues related to trial participation. REG X 25 Investigational Plan: Section 9.6- 9.8 Planned in the Protocol Training Statistical Analysis Quality Monitoring Control Quality Sample sizes Assurance Changes in the conduct of the study or planned analysis REG X 26  10. Study Patients Clinical Patients Treatment study Clear accounting of all patients who entered the study should be done. The numbers of patients who were randomised, and who entered and completed each phase of the study (lost to follow-up, adverse event, poor compliance etc.) should be provided. REG X 27 10.2 Protocol Deviations: Inclusion & Exclusion DEVIATIONS  Those who entered the study even though they did not satisfy the entry criteria.  Those who developed withdrawal criteria during the study but were not withdrawn.  Those who received the wrong treatment or incorrect dose.  Those who received an excluded concomitant treatment. REG X 28 PROTOCOL DEVIATIONS:- Mentimeter code 6494 8476 https://www.menti.com/alonqx7apzoj  Which of the following is example of protocol deviation:-……………….  A) Enrolling a participant who did not meet all the inclusion/exclusion criteria  B) Performing a study procedure approved by the IRB and not failing to perform a required lab test;  C) A and B are correct  D) None of the above is correct. REG X 29  11. Efficacy Measurements of compliance Efficacy results Clinical study Efficacy (statistical and Treatment analytical) patients analysis Drug-Drug and drug – disease interactions Primary and Secondary Endpoints Demographic and other baseline characteristics Group data for the critical demographic and baseline characteristics of the patients should be described. REG X 30 CLINICAL ENDPOINT: Primary endpoint: The specific event that the study is designed to assess the effect of the drugs upon. The primary endpoint is important to study design because the sample size required in order to adequately power a study is dependent on the number of primary events that are expected to occur over a given time period. Secondary endpoints: these are additional events of interest, but which the study is not specifically powered to assess because the design of the study was not based around the secondary endpoint (s), analyses of secondary endpoints need to be viewed with caution. REGX 31 12. SAFETY EVALUATION Analysis of safety-related data can be considered at three levels;- Extent of exposure SAFETY Common adverse events, EVALUATION Laboratory test changes Serious adverse events Significance adverse events Identification should be done by close examination of patients who left the study prematurely because of an adverse event, whether or not identified as drug related, or who died. REG X 32 ICH E3 Guideline: Questions and Answers REG X 33 13. DISCUSSION AND OVERALL CONCLUSIONS  The efficacy and safety results of the study and the relationship of risks and benefit should be briefly summarized and discussed, referring to the tables, figures, and sections above as needed. (14-15) 16. APPENDICES Protocol & Amendments Case Report Forms Adverse Events Safety Data Listings  This section should be prefaced by a full list of all appendices available for the study report. Where permitted by the regulatory authority, some of the appendices need not be submitted with the report but need to be provided only on request. REG X 34 CASE REPORT FORMS: is designed to collect the patient data in a clinical trial;  Adverse Events  Demographics FormRandomization Form  Serious Adverse Event (SAE) Report Form  Social History Form  Study Completion Form  Visit Checklist  Vital Signs  Inclusion/Exclusion Criteria  Medical History Form  Physical Exam  Prior and Concomitant Medications REG X 35  Example of Case Report Form: X REG 36 ANNEXES  ANNEX I Synopsis  Annex II Principal or Coordinating Investigator(s) Signature(s) or Sponsor’s Responsible Medical Officer  Annex III Study Design and Schedule of Assessments  Annex IV Disposition of Patients  ANNEX V Listing of Patients Who Discontinued Therapy  ANNEX VI Listing of Patients and Observations Excluded from Efficacy Analysis  ANNEX VII Number of Patients Excluded from Efficacy Analysis  ANNEX VIII Guidance for Section 11.4.2 - Statistical/Analytical Issues and Appendix 16.1.9 REG X 37 Conclusion  Upon completion of a clinical trial, the sponsor is required to prepare a detailed report on the study.  The content of CSRs is detailed in the ICH guideline E3.  It is important to understand the clinical and statistical description, presentations and analyses of the completed study. As regulator is important to understand all aspects of this crucial document in the drug development and regulatory submission process. REG X 38 RECAP OF TODAYS LESSON: What is the take away of todays presentation?? (Any one can comment) REGX 39  THANK YOU FOR YOUR ATTENTION! X GHPP PharmTrain 2 40